Sharon English Urologist Christchurch Taking the Wrinkles out of the Bladder The Use of Botulinum Toxin in the Bladder Sharon English Urologist Christchurch

After I started botoxing I just could not stop

Medical Uses of Botulinum Toxin blepharospasm pelvic pain strabismus achalasia focal dystonias muscle spasms spasticity wrinkles hyperhidrosis bladder overactivity painful bladder migraine 1949 recognised that Botulinum toxin blocked nerve synapses first medical use in stabismus and blepharospasm

Clostridium botulinum spore prior to germination The lethal dose of botulinum toxin for humans is not known but can be estimated from primate studies. By extrapolation, the lethal amounts of crystalline type A toxin for a 70-kg human would be approximately 0.09-0.15 µg intravenously or intramuscularly, 0.70-0.90 µg inhalationally, and 70 µg orally.10, 39-41 Therapeutic botulinum toxin represents an impractical bioterrorist weapon because a vial of the type A preparation currently licensed in the United States contains only about 0.3% of the estimated human lethal inhalational dose and 0.005% of the estimated lethal oral dose. All forms of botulism result from absorption of botulinum toxin into the circulation from either a mucosal surface (gut, lung) or a wound. Botulinum toxin does not penetrate intact skin

Botulinum Toxin A (Botox®) 7 distinct types Botulinum toxin A,B,C,D,E,F,G Type A and B used in medicine

Mechanism of Action of Botulinum Toxin Figure 1. Mechanism of Action of Botulinum Toxin A, Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane. The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syntaxin. After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell. B, Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. The light chain of botulinum toxin cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release. Botulinum toxins types B, D, F, and G cleave synaptobrevin; types A, C, and E cleave SNAP-25; and type C cleaves syntaxin. Without acetylcholine release, the muscle is unable to contract. SNARE indicates soluble NSF-attachment protein receptor; NSF, N-ethylmaleimide-sensitive fusion protein; and SNAP-25, synaptosomal-associated protein of 25 kd.

Mechanism of Action of Botulinum Toxin blocks neuromuscular conduction binds to receptor sites on motor nerve terminals inhibits release of acetylcholine (ACh) Inhibition involves cleavage of SNAP-25, a protein necessary for the release of ACh from vesicles within nerve endings. Results in a partial chemical denervation causing a localised paralysis

Regrowth of Axons

Uses of Botulinum Toxin in Urology and Gynaecology neuropathic bladder conditions detrusor overactivity detrusor sphincter dysenergia bladder overactivity painful bladder syndrome pelvic pain outflow obstruction symptoms urinary retention

Injecting Botulinum into the Bladder 100 units diluted with 10mls of normal saline given as 1 ml injections dose of 100 - 300 units spare the trigone

Injecting Botulinum Toxin Rigid cystoscope using GA day patient higher doses more precise Flexible cystoscope using LA outpatient clinic well tolerated

Injecting Botulinum toxin

Flexible Cystoscopy

Injection of Botulinum Toxin in the Bladder

Side Effects Very rare Contraindications no severe effects reported minor effects dysphagia, diplopia, blurred vision periheral muscle weakness Contraindications pre-existing neuromuscular conditions

Bladder Overactivity Collection of Symptoms urgency urge incontinence frequency nocturia Very common problem especially in the elderly

Treating Bladder Overactivity Treatment oxybutynin imipramine very expensive anticholinergics major surgery Now can offer Botulinum toxin if medications do not work

Choosing the Botox Patient Symptoms of urgency, urge incontinence No UTIs Failed/intolerant oxybutynin No voiding dysfunction Urodynamics

Urodynamics showing Detrusor Overactivity

Treating Bladder Overactivity with Botulinum Toxin Effects take 1-3 weeks Check residual if symptoms worsen Retention improves after 6-8 weeks UTIs Effects last 6-16 months Can repeat treatment

Literature Results 100 units 200 units Urge incontinence resolved 86% Nocturia 4 – 1.5 Frequency 14 – 7 Retention 4% 200 units Urge incontinence resolved 50% Nocturia Frequency 15 – 8 Retention 37%

Repeat Treatments Effect on smooth muscle Repeat treatments results in fades after 6-12 months axonal regeneration Repeat treatments results in same response antibodies to Type A very uncommon

Neurogenic Detrusor Overactivity Occurs in spinal cord injury multiple sclerosis Parkinson’s post-stroke

Neurogenic Detrusor Overactivity

Neurogenic Detrusor Overactivity 10 unit injections Use a higher dose: 300 units Patients already self-catheterising

Painful Bladder Syndrome Two studies one effective one ineffective Tried two patients with mixed effect Raises questions as to how Botulinum toxin works